Current challenges and future opportunities in patient‐focused management of hereditary angioedema: A narrative review

Abstract Patients with hereditary angioedema (HAE) experience a high burden of disease due to unpredictable, painful, disfiguring, and potentially life‐threatening HAE attacks. Multiple HAE‐specific medications for the on‐demand treatment, short‐term and long‐term prophylaxis of HAE attacks have entered the market in recent years; however, the availability and access to these medications may vary between different countries. For this review, PubMed and EMBASE databases were searched for guidelines, consensus statements, and other publications on HAE management as well as publications on quality of life in patients with HAE. The current guidelines and recent literature on HAE management in specific countries are summarized with the aim to highlight the similarities and differences between guideline recommendations and the country‐specific clinical practice. Improvement in quality of life, which is a key goal in HAE management, is also discussed and the country‐specific trends are highlighted. Finally, the ways to achieve a more patient‐centric approach to HAE management within the framework set by the clinical management guidelines are examined.

is also similar to that of acquired recurrent angioedema without urticaria, different types of which include acquired angioedema with C1-INH deficiency; angiotensin-converting enzyme inhibitor (ACEi) associated acquired angioedema; and acquired idiopathic histaminergic or non-histaminergic angioedema. 6 HAE attacks place a significant burden on the patient. Subcutaneous attacks can cause substantial short-term disability and disfigurement; abdominal attacks are painful and are sometimes mistaken for acute abdominal emergencies such as appendicitis, leading to unnecessary surgical procedures; and laryngeal attacks can cause death by asphyxiation. 2 Although HAE cannot be cured, pharmacologic management of HAE is available, with the goals of achieving disease control and ensuring that patients are not experiencing limitations from HAE symptoms. 4,[7][8][9] The pharmacologic treatment of HAE can be divided into three categories: on-demand treatment, short-term prophylaxis (STP), and long-term prophylaxis (LTP). 4 On-demand treatment is the treatment of attacks as soon as they become apparent and is used to reduce the severity, duration, and associated morbidity of HAE attacks and prevent potential mortality. [8][9][10] STP is used to minimize the risk of HAE attack occurring in situations where higher risk of HAE attacks is expected, such as before medical or dental procedures. The medication for STP of HAE attacks may be administered either just before or up to several days before the predictable trigger, depending on the type of medication used for STP. 4,9,10 Finally, LTP of HAE attacks is the routine use of medication to reduce the burden of disease by preventing occurrence of HAE attacks. 4,10 The armamentarium for LTP of HAE attacks has considerably expanded since 2017, with a subcutaneous formulation of plasmaderived C1-INH (pdC1-INH) approved in the United States in 2017 and the European Union (EU; approval date varies per country), 11,12 subcutaneous monoclonal antibody against plasma kallikrein lanadelumab approved both in the United States and the EU in 2018, 13,14 and oral kallikrein inhibitor berotralstat approved in the United States in 2020 and in the EU in 2021. 15,16 New and upcoming treatment options allow treatments to be tailored to individual patients. The aim of this narrative review is to discuss the challenges to patient-centric approaches for HAE management and the opportunities in this field within the context of current treatment guidelines.

| METHODS
To assess the current knowledge of HAE management, PubMed and EMBASE databases were searched for consensus statements and guidelines on HAE, as well as for studies from 2016 to 2021 reporting on the management of patients with HAE and/or quality of life (QoL) in patients with HAE.

| Guideline recommendations on clinical management of HAE
In recent years, multiple international 4,10,17 and national 8,9,[18][19][20][21][22] guidelines on the management of HAE as well as several consensus papers 7,23-28 on different aspects of HAE management were published ( Figure 1). Overall, these guidelines and consensus papers provide similar recommendations for the pharmacological treatment of HAE Type 1/2 (see Table 2 for detailed summary).
One of the recommendations is to consider on-demand treatment for all HAE attacks, with special emphasis placed on treating any HAE attacks affecting or potentially affecting the airway. 4,[8][9][10]22 It is recommended that all patients with HAE should have at least two doses of on-demand medication easily accessible to them at all times. 4,8,9,20,22 C1-INH, icatibant, and ecallantide (where available) are the recommended therapies for on-demand treatment of HAE attacks; fresh frozen plasma (FFP) is an option only when these treatments are not available. 4,[8][9][10]20,22,24 Attenuated androgens and antifibrinolytics are not recommended for on-demand treatment of HAE attacks. 4,9,10 The guidelines recommend to consider STP before medical, surgical, or dental procedures, as well as before events that could cause HAE attacks. 4,[8][9][10]20,22 In particular, procedures involving mechanical impact to upper respiratory or digestive tracts, including but not limited to: facial surgery; invasive dental treatment (dental surgery, tooth extraction); bronchoscopy; esophagogastroduodenoscopy; tonsillectomy; and surgical procedures requiring endotracheal intubation, may warrant consideration for STP. 4,9,10,22 As there is a lack of data regarding the risk of specific procedures, expert clinical judgment and individualized risk assessment are important when making decisions of when to administer STP. 4,9,10,22 The considerations on when to administer STP may include the degree of physical trauma involved with a specific procedure and whether the individual patient has history of HAE attacks under similar circumstances. 9,10,22 Additionally, the 2021 WAO/EAACI guidelines highlighted that the need for STP may be different in patients who already are receiving LTP of HAE attacks, although no specific recommendations were given due to lack of data. 4 C1-INH is the recommended treatment for STP of HAE attacks. 4,[8][9][10]20,22 FFP and androgens can be used as a second-line therapy for STP, although the 2020 US HAE guidelines include androgens among first-line options for STP of HAE attacks, along with C1-INH. 4,9,20,22 Furthermore, on-demand treatment should be available regardless if STP was administered or not. 4,10 Additional considerations may apply in countries where access to C1-INH is challenging, thus limiting C1-INH use both as STP and as ondemand treatment; for example, C1-INH is not easily accessible in Brazil's National Health System despite being approved as ondemand treatment and STP of HAE attacks, and overall access to on-demand treatment is very limited in Brazil. 22 The 2022 Brazilian guidelines for HAE therefore recommend C1-INH for STP of procedures perceived to be high-risk if C1-INH is available, and attenuated androgens or FFP when C1-INH is not available. For procedures perceived to be low-risk, the 2022 Brazilian guidelines for HAE suggest observation if on-demand medication is available and attenuated androgens when it is not. 22 Guideline recommendations on the timing and dosing of STP medications are summarized in Table 2, although available dosing in different countries may vary based on the local labeling. Briefly, the guidelines recommend administering C1-INH from <1 h before to 1-12 h before the procedure (the recommended timing varies in different guidelines). Androgens for STP of HAE attacks are recommended for 5-7 days before and 2-5 days after the procedure. 4,9,10,22 According to the guidelines, decisions to start or continue LTP should consider the efficacy and safety of the treatment, disease control, patients' QoL, and patient preference. Furthermore, the decision to start or continue LTP should be reviewed regularly as the patients' circumstances may change over time. 4,9,10,22 The first-line therapies for LTP of HAE attacks include C1-INH, 4,[8][9][10]20,22 lanadelumab, 4,9,10,20,22 and berotralstat. 4 Antifibrinolytics and attenuated androgens are second-line treatment options for LTP, although the 2021 WAO/EAACI guidelines on HAE management do not recommend the use of antifibrinolytics for LTP of HAE attacks. 4,9,10,20,22 Compared with HAE Type 1/2, nC1-INH-HAE is a rarer form of HAE. Given the rarity of nC1-INH-HAE and lack of robust evidence on the efficacy and safety of HAE medications in this population, the guideline recommendations for management of patients with nC1-INH-HAE are scarce ( STP is recommended for medical procedures related to pregnancy, such as chorionic villus sampling and amniocentesis. 4,9,10,22 STP is also recommended when undergoing cesarean section; however, it is not usually required for uncomplicated vaginal delivery, with a caveat that on-demand treatment should be readily available. 4

| Management of HAE in pediatric patients
Management of HAE in pediatric patients (aged <18 years) also requires additional considerations (Table 5). Country and patients' age must be taken into the account as well since the age groups for which the treatment options recommended by international guidelines are approved may vary per country. 10

| HAE treatment patterns in specific countries
The guideline recommendations for newer HAE-specific therapies are consistent; however, these therapies may be unavailable or difficult to access in some countries due to lack of local approvals or prohibitively high costs. This disparity in HAE treatment availability between countries has been recently summarized by Jindal et al. 35 Furthermore, the availability of published data on HAE treatment patterns also varies among countries ( Figure 2 obtained benefit from their use. 10 In these cases, lowest effective dose is recommended to avoid side effects, and maximum daily dose (200 mg for danazol, as per expert consensus) should not be exceeded. 4,9,10,22 In line with lack of approvals and/or limited availability for HAE-specific medications, studies from multiple countries only reported the use of attenuated androgens and tranexamic acid for LTP in HAE. These included studies from Brazil, 51,52 China, 53,54 Israel, 55 Italy, 56 Korea, 46 Poland, 57 Romania, 49 South Africa, 44 Turkey, 50 and Switzerland. 48  Shared decision-making is instrumental in developing individualized treatment plans that take account of disease activity as well as the individual patient's life circumstances and preferences. 4,7,9,27 To support with shared decision-making in HAE, a 3D (Discover, Discuss, Decide) framework has recently been adapted specifically for use in the HAE setting. 79 Given the high variability of HAE, such individualized treatment plans are crucial, and the guidelines and consensus statements recommend periodic review of these treatment plans. 4,9,27 QoL is emphasized as a key factor for consideration in shared decision-making and individualized treatment plans. 4 60,85 Another limitation that patients with HAE may experience is a reduction in work productivity. In an international survey, patients reported 25% presenteeism, 24% work productivity loss, and 34% activity impairment. 62 Similarly, a study from Canada reported 31% absenteeism, 27% work productivity loss, 10% presenteeism, and 21% activity impairment. 81 In a study from the United States, diminished work productivity was associated with higher numbers of HAE attacks (3.3% work productivity loss in patients who were attack free for 6 months vs. 52.5% in those experiencing ≥13 attacks). 39 Work productivity impairment, absenteeism, and presenteeism were the highest in attacks that affected the face; activity impairment was highest with abdominal and laryngeal attacks (76.7%). 39 In addition to interfering with work productivity, disease activity was also reported to affect QoL in patients with HAE. Higher number or higher frequency of HAE attacks were associated with lower QoL in studies conducted in the United States, 39 Canada, 86 Hungary, 87 and Hungary and Israel. 84  and a study from Germany reported significantly better QoL and reduced anxiety and depression in patients who were receiving LTP compared with patients who were receiving on-demand treatment only. 89 One of the studies from the United States also reported socioeconomic costs (including lower work productivity, presenteeism, absenteeism, and lower labor market participation) associated with on-demand treatment only, suggesting that LTP of HAE attacks could be associated with reduction of these costs. 43  unspecified) as well as those receiving any LTP and those without, and found no differences; however, numerical data for these comparisons were not reported. 86 In the studies from the United States and Germany that reported higher QoL in patients receiving LTP, 62%-89% of patients who received LTP were using first-line options (C1-INH or lanadelumab) for their LTP. 41,43,89 In contrast, in a study from China that did not detect QoL differences in patients receiving and not receiving HAE prophylaxis, all patients were receiving second-line option (androgens) for their LTP; other studies reporting no association between LTP and QoL did not report what medications were used for LTP. 53,81,86,91 As androgen use is often associated with side effects and comorbidities (eg, in a study from Switzerland, 54% of patients who were receiving LTP with danazol and 24% of those who were not reported comorbidities), these could obfuscate the impact of reduced HAE attack rate on QoL and contribute to amplified cost of care. 48,92 It should be noted that other HAE medications may also be associated with a treatment burden that could be masking the effect of reduced attack number on QoL. In several studies from the United States, patients reported anxiety around taking their HAE medication, 41 finding needles and/or injections/infusions unpleasant, 38 and being tired of injections/infusions. 38,41 However, the majority of patients also reported learning to cope with the difficult aspects of their HAE treatment and being satisfied with their current injectable medications. 40,41 Additionally, injectable medications for HAE have longer dosing intervals, which have been associated with higher treatment adherence in several different therapeutic areas, presumably due to more patient convenience with less frequent dosing. 93